Blood-oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) can be used to visualize the localized hemodynamic changes in brain which occur in response to drug-induced changes in brain activation. The objective of this proposal is to use this technique to measure changes in brain activation that occur during and after smoking tobacco and placebo cigarettes. Few studies have been reported which have measured the impact of nicotine or placebo on brain activation using BOLD fMRI. None of these have used smoked cigarettes. A magnetic resonance (MR)-compatible smoking device has been developed at McLean Hospital Brain Imaging Center that can be used to allow smoking by subjects with concurrent MR imaging. Additionally, it has been repeatedly shown that conditioned reinforcers, such as the taste and smell of smoke, as well as airway sensations associated with smoking serve as powerful reinforcers in nicotine dependent individuals. The studies outlined here are designed to separate these conditioned reinforcers from the primary reinforcing effects of nicotine, and evaluate their impact on BOLD fMRI signal. OBJECTIVE: To use blood oxygen level dependent functional magnetic resonance imaging to visualize local hemodynamic changes in brain during the smoking of tobacco or placebo cigarettes and during nicotine and saline infusion. Subjective ratings of drug effect will also be measured throughout the imaging session. Experiments involving manipulations of nicotine withdrawal status and nicotine dependence state will yield data that will reveal the impact of both these factors on the acute effects of smoked or injected nicotine or placebo on both smoking-induced BOLD changes and subjective ratings of drug effect. SPECIFIC AIM 1 Evaluate the time course of changes in BOLD signal and subjective ratings of drug effect in response to smoked tobacco: Effects of abstinence and dependence. SPECIFIC AIM 2: Evaluate the time course of changes in BOLD signal and subjective ratings of placebo effect in response to smoked placebo tobacco: Effects of abstinence and dependence. SPECIFIC AIM 3: Evaluate the time course of changes in BOLD signal and subjective ratings of drug effect in response to i.v. nicotine or saline infusion in abstinent nicotine dependent smokers. RATIONALE: Previous neuroimaging studies of the effects of nicotine have used routes of administration other than smoking. Since smoking provides the most rapid onset of drug effects and since smoking is the method of nicotine administration used by smokers (often tens of times daily), a better understanding of the effects of smoked nicotine and the impact of conditioned reinforcers associated with smoking on a correlate of brain activation during smoking is crucial. The idea that withdrawal and dependence may influence this effect is supported by previous clinical and preclinical studies. Smoking is the leading preventable cause of death. Despite decades of research, there are no effective treatments for cigarette addiction. A better understanding of the effects of smoked nicotine and placebo in living human brain may provide clues to guide development of rational and efficacious treatments. [unreadable] [unreadable] [unreadable]